Leucovorin (LV) pharmacokinetics in patients receiving high dose methotrexate (HDMTX), with or without glucarpidase treatment.

e20521 Background: Glucarpidase is a recombinant form of carboxypeptidase G2 and hydrolyzes MTX into inactive metabolites and provides alternate clearance in pts with delayed elimination and acute kidney injury. It is administered with IV hydration, urinary alkalinization, and LV. The primary objective was to investigate whether glucarpidase reduces exposure to LV and its active metabolite (5EMeTHF) to below the level achieved in pts who have not received glucarpidase, by assessing the PK of the active L-isomer of LV (6S-LV) following administration of HDMTX and LV. Methods: Open-label, multicenter PK study in pts treated with HDMTX (≥1 g/m2) and LV (either ≥15 mg or ≥10 mg/m2) with subsequent glucarpidase where indicated for renal impairment (Arm A) or without glucarpidase (Arm B). Plasma samples for LV and 5EMeTHF were taken pre-LV and at 5, 30, 60, 120, and 180 min after LV to calculate the area under the concentration curve of 6S-LV over 0-3 hours (AUC0-3) following the LV dose. Results: 17 pts (8 Arm A, 9 Arm B) were analyzed. The median pre-glucarpidase methotrexate (MTX) plasma concentration was higher for Arm A 7.5 µmol/L) than B (1.1 µmol/L). Similarly, median LV doses were 89.88 mg/m2 (Arm A) and 13.51 mg/m2(Arm B). Mean 6S-LV AUC0-3 values (µmol*h/L) for Arm A were 8.70±5.56, compared with 1.31±0.78 for Arm B, consistent with Arm A receiving a higher LV dose than Arm B. Mean 6S-5MeTHF AUC0-3 values (µmol*h/L) were similar in arms A and B (0.68 and 0.73). When normalized for LV doses, mean 6S-LV AUC0-3values (µmol*h/L) were similar between arms:10.02±4.83 in Arm A versus 9.79±5.18 for Arm B. Conclusions: Glucarpidase does not reduce exposure to 6S-LV and 5-MeTHF to below the level achieved in patients with normal renal function who did not receive glucarpidase. Adequate LV exposure is achieved if LV dosing is based on pre-glucarpidase plasma MTX concentration for at least 48 hours after glucarpidase administration. Clinical trial information: NCT00634504.